International Verapamil-Trandolapril Study - INVEST


The goal of the International Verapamil-Trandolapril Study (INVEST) was to determine the efficacy and safety of a calcium antagonist-based blood pressure (BP) lowering strategy versus a noncalcium antagonist-based strategy in hypertensive coronary artery disease (CAD) patients.


Treatment with a calcium antagonist-based BP lowering strategy is equivalent to treatment with a noncalcium antagonist-based strategy in hypertensive patients with CAD with regard to the composite of death, myocardial infarction (MI), or stroke.

Study Design

Study Design:

Patients Screened: 23,482
Patients Enrolled: 22,576
Mean Follow Up: Mean 2.7 years
Mean Patient Age: Mean age 66 years
Female: 52

Patient Populations:

Hypertension by JNC VI criteria requiring drug therapy, CAD, and age ≥50 years


Recent MI, unstable angina, chronic heart failure (class IV), and those with contraindication to study medications

Primary Endpoints:

Composite of death (all-cause), nonfatal MI, or nonfatal stroke

Secondary Endpoints:

CV death, nonfatal and fatal stroke, nonfatal and fatal MI, angina frequency, and CV hospitalization

Drug/Procedures Used:

Hypertensive patients were randomized to either the calcium antagonist verapamil SR (n=11,267) or the noncalcium antagonist atenolol (n=11,309) at 862 international sites. The treatment strategies consisted of flexible regimens (dose and additional drugs), as needed for optimal BP control, based on the sixth Joint National Commission (JNC VI) guidelines.

The angiotensin-converting enzyme (ACE) inhibitor trandolapril and/or the diuretic hydrochlorothiazide were available in both strategies. The BP goals were <140/<90 mm Hg or <130/<85 for diabetes or renal dysfunction. The trial was open-label, but clinical events were determined by a blinded, adjudicated events committee.

Concomitant Medications:

Approximately 60% of the patients required two or more antihypertensive drugs.

Principal Findings:

Use of randomized treatment at two-year follow-up was 82% in the verapamil arm and 78% in the atenolol arm, with a crossover of 11.6% and 16.5%, respectively (p<0.0001). Trandolapril was used in 63% of patients in the verapamil arm and 52% in the atenolol arm, with hydrochlorothiazide used in 44% and 60% of patients, respectively. More than half of the patients were using three or more drugs (51% and 52%, respectively).

Systolic BP targets were met in 64.9% and 64.3% of patients, respectively (p=0.38) and diastolic BP targets in 90.7% in each arm. There was no difference in the primary endpoint of survival free of stroke or MI at follow-up (9.9% vs. 10.2%, relative risk 0.98, 95% confidence interval 0.90-1.06, p=0.57), meeting the prespecified equivalence parameters.

The individual components of the composite for the verapamil versus atenolol arms are: death 7.75% versus 7.90%, p=0.72; nonfatal MI 1.34% versus 1.35%, p=0.95; and nonfatal stroke 1.16% versus 1.31%, p=0.33. There were also no differences in cardiovascular (CV) deaths (3.83% vs. 3.81%, p=0.94) or CV hospitalizations (6.44% vs. 6.27%, p=0.59).

New onset diabetes occurred less frequently in the verapamil arm (7.03% vs. 8.23%, p<0.05), although this was not a prespecified endpoint and was only collected after the trial began. When new onset diabetes was combined with the primary composite event of death, MI, or stroke, a benefit was observed in the verapamil arm (14.63% vs. 16.25%, p<0.05).


Among hypertensive CAD patients, treatment strategy with the calcium antagonist verapamil was associated with equivalency in the primary composite endpoint of all-cause mortality, MI, and stroke compared with treatment with a noncalcium antagonist strategy with atenolol. More than half of the patients in each arm were treated with three or more drugs, an indication of the complexity of therapy required in these patients with both hypertension and CAD. Both therapies showed similar efficacy in reaching the target BP goals.

The lower rate of new onset diabetes in the calcium antagonist arm was noteworthy. However, this was not a prespecified endpoint and should be considered as a hypothesis-generating analysis, rather than an analysis to make conclusions on treatment effect.

It is unclear if the lower diabetes rate was due to a protective effect of the ACE inhibitor used as the second drug in the calcium channel blocker (CCB) arm or if hydrochlorothiazide use, which was more frequent in the non-CCB arm, may have resulted in an increase in diabetes in the non-CCB arm. Further trials may be warranted. A notably larger percentage of patients enrolled in the trial were female than in earlier trials.


Pepine CJ, Handberg EM, Cooper-DeHoff RM, et al. A calcium antagonist vs a non-calcium antagonist hypertension treatment strategy for patients with coronary artery disease. The International Verapamil-Trandolapril Study (INVEST): a randomized controlled trial. JAMA 2003;290:2805-16.

Presented at Late-Breaking Clinical Trials, ACC 2003.

Presented at the European Society of Cardiology, Vienna, Austria, September 2003.

Keywords: Risk, Coronary Artery Disease, Myocardial Infarction, Stroke, Follow-Up Studies, Diuretics, Calcium Channel Blockers, Indoles, Hydrochlorothiazide, Verapamil, Confidence Intervals, Hypertension, Diabetes Mellitus

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